MicrobiologyBytes

In PNAS, Warren Olanowa and Stanley Prusiner ask, Is Parkinson’s disease a prion disorder?
Parkinson’s disease (PD) is an age-related, neurodegenerative disease that affects approximately one million people in the United States. Pathologically, the disease is characterized by a loss of dopamine neurons in the substantia nigra coupled with proteinaceous inclusions in nerve cells and terminals, known as Lewy bodies and Lewy neurites, respectively. PD pathology is also known to affect nondopamine neurons in the upper and lower brainstem, olfactory system, cerebral hemisphere, spinal cord, and autonomic nervous system. The cause of cell death in PD is not known, but proteolytic stress with the accumulation of misfolded proteins has been implicated.

In the current issue of PNAS, Desplats et al demonstrate that nerve cells which overexpress tagged alpha-synuclein can transmit the protein to neural stem cells in both in vitro and in vivo models (Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. 2009 PNAS USA 106:13004–13005). This important study could explain the remarkable finding that human embryonic dopamine nerve cells implanted into the striatum of patients with PD develop PD pathology with loss of dopamine markers and classic Lewy bodies. It also provides insight into how alpha-synuclein pathology might sequentially spread throughout the nervous system in PD.

It is thus possible that PD is a prion disorder resulting from increased production and/or impaired clearance of proteins such as alpha-synuclein, leading to misfolding and the formation of toxic oligomers, aggregates, and cell death. Further, it is possible that alpha-synuclein is a prion protein that can self-aggregate and be transmitted to unaffected cells, thus extending the disease process. While genetic causes represent an obvious source of increased levels of aberrantly folded alpha-synuclein in familial PD cases, a combination of aging, oxidative stress, inflammation, environmental toxins, hereditary factors, and impaired clearance may all feature in varying ways in causing altered metabolism of alpha-synuclein, resulting in the pathogenesis of sporadic PD. This concept suggests that drugs directed toward reducing the formation and/or facilitating the clearance of misfolded alpha-synuclein, so as to arrest or reverse the self-propagation process, might represent a novel therapeutic interventions for the treatment of PD.

Related:

• Stanley Prusiner at the SGM: Prion Biology and Diseases
• What the heck are prions for?
• Drugs for treatment of prion infections
• Alzheimer’s Disease and Prions

Studies using model organisms have pointed to the existence of evolutionarily conserved genes and signaling pathways that regulate life span. Changes in the activity of these genes/pathways have also been implicated in mediating the beneficial effect of calorie restriction, a well recognized intervention that extends the life span from yeast to mammals. Researchers investigated the global gene expression changes and identified genes involved in the metabolism of various kinds of carbon sources that are associated with longevity in the single cell organism, the baker’s yeast Saccharomyces cerevisiae. Although glucose and ethanol are common carbon sources for growth, they also have detrimental pro-aging effects in yeast. Long-lived yeast mutants actively utilize available glucose and ethanol and produce glycerol, which does not adversely affect the yeast life span extension. New findings suggest that this “carbon source substitution” observed in long-lived yeast creates an environment mimicking calorie restriction, which together with the direct regulation of stress resistance systems optimizes life span extension.

Yeast maintained on a glycerol diet live twice as long as normal – as long as yeast cells on a severe caloric-restriction diet. They are also more resistant to cell damage. Many studies have shown that caloric restriction can extend the life span of a variety of laboratory animals. Caloric restriction is also known to cause major improvements in a number of markers for cardiovascular diseases in humans. This study is the first to propose that “dietary substitution” can replace “dietary restriction” in a living species. If you add glycerol, or restrict caloric intake, you obtain the same effect. This is as effective as calorie restriction, yet cells can take it up and utilize it to generate energy or for the synthesis of cellular components.

The researchers investigated the effect of a glycerol diet after discovering that genetically engineered long-lived yeast cells that survive up to 5-fold longer than normal have increased levels of the genes that produce glycerol. In fact, they convert virtually all the glucose and ethanol into glycerol. Notably, these cells have a reduced activity in the TOR1/SCH9 pathway, which is also believed to extend life span in organisms ranging from worms to mice. When the researchers blocked the genes that produce glycerol, the cells lost most of their life span advantage. However, the “glucose to glycerol” switch is believed to represent only one component of the protective systems required for extended survival. This study indicates that glycerol biosynthesis is an important process in the metabolic switch that allows this simple organism to activate its protective systems and live longer. This is a fundamental observation in a very simple system, that at least introduces the possibility that you don’t have to be calorie-restricted to achieve some of the remarkable protective effects of the hypocaloric diet observed in many organisms, including humans. It may be sufficient to substitute the carbon source and possibly other macronutrients with nutrients that do not promote the “pro-aging” changes induced by sugars. Findings using these simple genetic models should help to discover fundamental longevity regulatory mechanisms and identify similar pathways in mammals. Darn useful things, yeasts :-)

Tor1/Sch9-Regulated Carbon Source Substitution Is as Effective as Calorie Restriction in Life Span Extension. PLoS Genet 5(5): e1000467
The effect of calorie restriction (CR) on life span extension, demonstrated in organisms ranging from yeast to mice, may involve the down-regulation of pathways, including Tor, Akt, and Ras. Here, we present data suggesting that yeast Tor1 and Sch9 (a homolog of the mammalian kinases Akt and S6K) is a central component of a network that controls a common set of genes implicated in a metabolic switch from the TCA cycle and respiration to glycolysis and glycerol biosynthesis. During chronological survival, mutants lacking SCH9 depleted extracellular ethanol and reduced stored lipids, but synthesized and released glycerol. Deletion of the glycerol biosynthesis genes GPD1, GPD2, or RHR2, among the most up-regulated in longlived sch9D, tor1D, and ras2D mutants, was sufficient to reverse chronological life span extension in sch9D mutants, suggesting that glycerol production, in addition to the regulation of stress resistance systems, optimizes life span extension. Glycerol, unlike glucose or ethanol, did not adversely affect the life span extension induced by calorie restriction or starvation, suggesting that carbon source substitution may represent an alternative to calorie restriction as a strategy to delay aging.

Related:

• Psst – want to live forever?
• Yeast shows what drives cells to divide
• The Genetics of Beer
• Brewing Beer
• In Praise of Yeast